Inthezonafasciculata,cholesterolisconvertedsequentially to pregnenolone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, and cortisol (Figs. 43.8 43.9 ). A parallel pathway in the zona fasciculata involves a pathway that bypasses 17-hydroxylation, in which progesterone is converted to 11-deoxycorticosterone (DOC) and then to corticosterone (see
Fig. 43.9C ). This pathway is minor in humans, but in the absence of active CYP11B1 (11-hydroxylase activity), the production of DOC is significant. Because DOC acts as a weak mineralocorticoid ( 43.3 ), elevated levels of DOC cause hypertension.
Transport and Metabolism of Cortisol
Cortisol is transported in blood predominantly bound to corticosteroid-binding globulin [CBG] (also called transcortin), which binds about 90% of cortisol, and albumin, which binds 5% to 7% of cortisol. The liver is the predominant site of steroid inactivation. It both inactivates cortisol and conjugates active and inactive steroids with glucuronide or sulfate so that they can be excreted more readily by the kidney. The circulating half-life of cortisol is about 70 minutes.
Cortisol is reversibly inactivated by conversion to cortisone. This action is catalyzed by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Inactivation of cortisol by 11β-HSD2 occurs in cells that also express the mineralocorticoid receptor (MR)and are
Steroidogenicenzymesfallintotwosuperfamilies.Mostbelongtothecytochrome P-450 monooxidase gene family andarethusreferredtoasCYPs. Theseenzymesarelocatedeitherintheinnermitochondrialmatrix,wheretheyusemolecularoxygenandaflavoproteinelectrondonor,orinthesmoothendoplasmicreticulum,wheretheyuseadifferentflavoproteinforelectrontransfer.DifferentCYPenzymesactashydroxylases,lyases(desmolases),oxidases,oraromatases.Twooftheseenzymeshavemultiplefunctions.CYP17hasbotha17-hydroxylasefunctionanda17,20-lyase(desmolase)function.CYP11B2,alsocalledaldosterone synthase, hasthreefunctions:11-hydroxylase,18-hydroxylase,and18-oxidase.
Theotherenzymesinvolvedinsteroidogenesisbelongtothreehydroxysteroid dehydrogenase (HSD)families.3β-HSDs havetwoisoformsthatconvertthehydroxylgrouponcarbon3ofthecholesterolringtoaketoneandshiftthedoublebondfromthe5-6(Δ5) positiontothe4-5(Δ4) position.AllactivesteroidhormonesmustbeconvertedtoΔ4structuresby3β-HSD.The17β-HSDs haveatleastfivemembersandcanactaseitheroxidasesorreductases.17β-HSDsprimarilyactonsexsteroidsandcanbeactivatingordeactivating.Finally,the11β-HSDs havetwoisoformsthatcatalyzetheinterchangebetweencortisol(active)andcortisone(inactive).